Posaconazole (CAS Registry Number 171228-49-2; CAS Name: 2,5-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol) which is represented by the following general formula (I)
is known as an antifungal agent. It is available as an oral suspension (40 mg/ml) under the trademark NOXAFIL® from Schering Corporation, Kenilworth, N.J.
WO95/17407 and WO 96/38443 disclose the compound having the general formula (I) and its use in treating fungal infections.
A pharmaceutical composition comprising posaconazole, at least one non-ionic surfactant and a diluent is disclosed in WO 02/80678, e.g. in the form of a liquid suspension. WO 02/80678 also describes that for use in its suspension posaconazole is to be micronized, e.g. by microfluidization to obtain a specific particle size in the range of about 1000 nm (nanometers) to about 1800 nm to obtain enhanced bioavailability. The reduction of the particle size is carried out during the preparation of the posaconazole active ingredient and/or during the manufacture of the pharmaceutical composition. A solid solution of posaconazole, which can be provided in the form of a tablet or capsule, is disclosed in U.S. Pat. No. 5,972,381. Other pharmaceutical compositions prepared by mixing or granulating posaconazole with a non-ionic surfactant and a diluent which may be formulated into capsules or tablets are disclosed in U.S. Pat. No. 5,834,472. A topical form of posaconazole, e.g. a lotion, cream, ointment, or “lacquer nail polish” is described in U.S. Pat. No. 4,957,730 (PENLAC® available from Dermik®). An injectable pharmaceutical suspension comprising posaconazole that is stable when subjected to terminal steam sterilization is disclosed in WO 2005/117831.
As was mentioned above, WO 95/17407 and WO 96/38443 disclose the compound having the general formula (I). However, during prosecution of the subsequently filed European patent application no. 98951994.7, now European patent EP 1 021 439 B1, the applicant declared that the methods disclosed in these publications only lead to the compound of formula (I) as an amorphous solid.
Polymorphism is a phenomenon relating to the occurrence of different crystal forms for one molecule. There may be several different crystalline forms for the same molecule with distinct crystal structures and distinct and varying physical properties like melting point, XRPD spectrum, IR-spectrum and solubility profile. These polymorphs are thus distinct solid forms which share the molecular formula of the compound from which the crystals are made up, however, they may have distinct advantageous physical properties which can have a direct effect on the ability to process and/or manufacture the drug product, like flowability, as well as physical properties such as solubility, stability and dissolution properties which can have a direct effect on drug product stability, dissolution, and bioavailability.
Three polymorphic forms of posaconazole designated as forms I, II and III are described and characterized in WO 99/18097 (U.S. Pat. No. 6,713,481, U.S. Pat. No. 6,958,337). Crystalline forms II and III were found to be unstable under the conditions investigated, so that crystalline form I was considered to be useful in the development of a pharmaceutical product.
There remains a need for alternative polymorphic forms of posaconazole which are more stable than form I when used in a pharmaceutical composition and/or which have properties that make them suitable for bulk preparation and handling. Additionally, there is a need for alternative polymorphic forms of posaconazole which allow improved pharmaceutical processing such as the preparation of pharmaceutical compositions on a commercial scale, in particular without the need to apply time-consuming methods to reduce their particle size. Finally, it would be desirable to provide alternative polymorphic forms of posaconazole which show improved dissolution properties and enhanced bioavailability.